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140)
Rissardo J. P.; Caprara A. L. F.; Durante Í.
Prague Medical Report / Vol. 122 (2021) No. 3, p. 140–180
Valproate-associated Movement Disorder: A Literature ReviewJamir Pitton Rissardo1, Ana Letícia Fornari Caprara1, Ícaro Durante2
1Department of Medicine, Federal University of Santa Maria, Santa Maria, Brazil;2Department of Medicine, Federal University of Fronteira Sul, Passo Fundo, Brazil
Rece i ved February 21, 2020; Accepted August 22, 2021.
Key words: Valproate – Valproic acid – Review – Movement disorder – Drug-induced
Abstract: Valproate (VPA) was first synthesized in 1882, but it was only in the early 1960s that its anticonvulsant properties were discovered. The aim of this literature review is to evaluate the clinical epidemiological profile, pathological mechanisms, and management of VPA-associated movement disorder (MD). Relevant reports in six databases were identified and assessed by two reviewers without language restriction. A total of 138 reports containing 362 cases of subjects who developed a MD secondary to VPA were reported. The MD identified were parkinsonism (PKN) (252), myoclonus (MCL) (54), dystonia (DTN) (17), dyskinesia (DKN) (16), stutters (4), tics (3), akathisia (AKT) (1). In the not clearly defined group, 15 extrapyramidal symptoms, 3 AKT, 2 DTN, 1 rigidity, 1 unstable gait were assessed. The mean and median age was 55.8 (SD: 16.58) and 61 years (range: 4–87 years). The most common VPA-indication was epilepsy, and 51.36% were males. The mean and median time from the VPA start to the MD onset was 32.75 (SD: 30.05) and 21.15 months (range: 1 day – 20 years). The mean and median time from the VPA withdrawal until the MD recovery was 2.89 (SD: 2.79) and 3 months (1 day – 12 months). The most common management was drug withdrawal. A complete recovery was obtained in 80.61%. VPA-associated MD was extensively reported in the literature. PKN was the most well-described. Future studies need to clearly report the clinical history of the patient, considering the full investigation of other adverse events during their entire life.
Mailing Address: Dr. Jamir Pitton Rissardo, Av. Roraima, 1000 – Camobi, Santa Maria – RS, 97105-900, Brazil; Phone: (55) (55) 334 729 08; e-mail: [email protected]
https://doi.org/10.14712/23362936.2021.14 © 2021 The Authors. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0).
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IntroductionValproate (VPA), and its pharmacological forms such as valproic acid, sodium valproate, and valproate semisodium are anticonvulsants (Figure 1). In 1882, Beverly Burton synthesized VPA for the first time; this compound was used for almost eighty years as an inert solvent in laboratories (Lempérière, 2001). Pierre Eymard, in the early 1960s, during animal studies to develop a new antiepileptic drug, noted that the substances dissolved in VPA had apparently better anticonvulsant properties (Henry, 2003). After this observation, many clinical studies showed the efficacy and safety of VPA for the management of focal seizures (Brugger et al., 2016). In 1967, it was approved as an antiepileptic drug in France (Henry, 2003). Only in 1983, the Food and Drug Administration approved this medication for the treatment of epilepsy (Lempérière, 2001). The first study assessing the efficacy of VPA in bipolar disorder was done by Lambert et al. at the end of the 1960s in France, soon after the approval for epilepsy, which showed good results, but for many years these data were believed to be incidental, due to the small number of subjects studied (Henry, 2003). About ten years later, German clinical trials followed by North American studies supported the hypothesis of Lambert et al. In 1995, VPA was approved as monotherapy during manic episodes by the FDA (Lempérière, 2001).
The mechanism of action of VPA is not completely understood (Figure 2) (Lempérière, 2001; Löscher, 2002; Bowden, 2003; Henry, 2003; Brugger et al., 2016). Its main interactions are related to the voltage-gated sodium channels blockage and increased brain levels of gamma-aminobutyric acid (GABA) (Löscher, 2002). The increased concentration of this neurotransmitter is believed to occur due to indirect inhibition of the GABA’s reuptake and degradative enzymes. Also, it is worth mentioning that this GABAergic mechanism probably explains the anticonvulsant and antimanic properties of this drug (Bowden, 2003). Other pathways that VPA is related include the Kv7.2, AKAP5, and histone deacetylase (Löscher, 2002). It is hypothesized that the inhibition of the histone deacetylase may have neuroprotective effects due to the increased uncoiling of DNA promoting more transcriptional activity of chromatin structures (Bowden, 2003).
The adverse effects of this medication that affect more than ten percent of users are nausea, vomiting, headache, coagulation disorders (Rissardo et al.,
Figure 1 – Skeletal formula of the anticonvulsant drug valproic acid, also known as 2-propylvaleric acid.
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Prague Medical Report / Vol. 122 (2021) No. 3, p. 140–180
2019), alopecia, asthenia, somnolence, amblyopia, diarrhea, dizziness, dyspepsia, nystagmus, and tinnitus (Bowden, 2003). In the label of VPA, there is a black box warning about hepatotoxicity in susceptible individuals (those with mitochondrial diseases), teratogenicity, and pancreatitis (Löscher, 2002). Other common side effects secondary to VPA are movement disorders (MD) such as tremor and ataxia, which can significantly impact the quality of life of an important percentage of the VPA users. Moreover, these abnormal movements are challenging to diagnose and manage in the clinical practice, because the majority of affected individuals have a pre-existing psychiatric or neurologic comorbidity.
In the literature, there are few reviews about VPA and MD that were not focused solely on tremors. To be more specific, we found two reviews about VPA-induced parkinsonism (PKN). Mahmoud and Tampi published a study about this topic in 2011; they objectively selected elderly patients, and a total of thirteen case reports were analysed. In 2016, Brugger et al. searched on four databases for papers in English about VPA and PKN, a total of 116 patients were evaluated; their purpose was to discuss the possible hypotheses for these adverse effects. In this context, the aim of the present literature review is to evaluate the clinic-epidemiological profile, pathological mechanisms, and management of VPA-associated MD.
Figure 2 – Representation of proposed mechanisms of action for valproate (VPA). α-KGDH – alpha-ketoglutarate dehydrogenase; ABAT – 4-aminobutyrate aminotransferase; AspAT – aspartate aminotransferase; CaV3.1 – voltage-gated calcium channel; GABA – gamma-aminobutyric acid; GABAA/B-R – GABAA/B receptor; GAD – glutamate decarboxylase; GIRK – G protein-gated inwardly rectifying potassium channel; KV7.2 – voltage-gated potassium channel; NMDAR – N-methyl-D-aspartate receptor; SCS – succinyl CoA synthetase; SSA – succinic semialdehyde; SSDH – succinate-semialdehyde dehydrogenase; VGSC – voltage-gated sodium channel.
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MethodsSearch strategyWe searched six databases and also abstracts of the “International Congress of the Parkinson’s Disease and Movement Disorders (1990–2019)” in an attempt to locate any and all existing reports on movement disorders (MD) secondary to VPA published between 1975 and 2019 in electronic form. Excerpta Medica (Embase), Google Scholar, Latin American and Caribbean Health Sciences Literature (Lilacs), Medline, Scientific Electronic Library Online (Scielo), and ScienceDirect were searched. Search terms were “parkinsonism, dyskinesia, dystonia, stuttering, myoclonus, restless legs syndrome, akathisia, tremor, chorea, tics, restlessness, ataxia, ballism, hyperkinetic, hypokinetic, bradykinesia, movement disorder”. These terms were combined with “valproate, valproic acid” (Table 1).
Inclusion and exclusion criteriaCase reports, case series, original articles, letters to the editor, bulletins, and poster presentations published from 1975 to 2019 were included in this review with no language restriction. The authors independently screened the titles and abstracts
Table 1 – FreeText and MeSH search terms in the US National Library of Medicine
Category Search terms Results
Parkinsonism ((((((“valproate”[All Fields] OR “valproate’s”[All Fields]) OR “valproates”[All Fields]) OR “valproic acid”[MeSH Terms]) OR (“valproic”[All Fields] AND “acid”[All Fields])) OR “valproic acid”[All Fields]) OR “valproate”[All Fields]) AND (((((((((((“parkinson disease”[MeSH Terms] OR (“parkinson”[All Fields] AND “disease”[All Fields])) OR “parkinson disease”[All Fields]) OR “parkinson’s”[All Fields]) OR “parkinsons”[All Fields]) OR “parkinson”[All Fields]) OR “parkinsonian disorders”[MeSH Terms]) OR (“parkinsonian”[All Fields] AND “disorders”[All Fields])) OR “parkinsonian disorders”[All Fields]) OR “parkinsonism”[All Fields]) OR “parkinsonisms”[All Fields]) OR “parkinsons’s”[All Fields])
180
Tics ((((((“valproate”[All Fields] OR “valproate’s”[All Fields]) OR “valproates”[All Fields]) OR “valproic acid”[MeSH Terms]) OR (“valproic”[All Fields] AND “acid”[All Fields])) OR “valproic acid”[All Fields]) OR “valproate”[All Fields]) AND (“TIC”[Journal] OR “TIC”[All Fields])
15
Dyskinesia ((((((“valproate”[All Fields] OR “valproate’s”[All Fields]) OR “valproates”[All Fields]) OR “valproic acid”[MeSH Terms]) OR (“valproic”[All Fields] AND “acid”[All Fields])) OR “valproic acid”[All Fields]) OR “valproate”[All Fields]) AND ((((“dyskinesiae”[All Fields] OR “dyskinesias”[MeSH Terms]) OR “dyskinesias”[All Fields]) OR “dyskinesia”[All Fields]) OR “dyskinesis”[All Fields])
576
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Category Search terms Results
Dystonia ((((((“valproate”[All Fields] OR “valproate’s”[All Fields]) OR “valproates”[All Fields]) OR “valproic acid”[MeSH Terms]) OR (“valproic”[All Fields] AND “acid”[All Fields])) OR “valproic acid”[All Fields]) OR “valproate”[All Fields]) AND (((((“dystonia”[MeSH Terms] OR “dystonia”[All Fields]) OR “dystonias”[All Fields]) OR “dystonic disorders”[MeSH Terms]) OR (“dystonic”[All Fields] AND “disorders”[All Fields])) OR “dystonic disorders”[All Fields])
54
Stuttering ((((((“valproate”[All Fields] OR “valproate’s”[All Fields]) OR “valproates”[All Fields]) OR “valproic acid”[MeSH Terms]) OR (“valproic”[All Fields] AND “acid”[All Fields])) OR “valproic acid”[All Fields]) OR “valproate”[All Fields]) AND ((((((((((((“stammerers”[All Fields] OR “stammers”[All Fields]) OR “stutterer”[All Fields]) OR “stutterer’s”[All Fields]) OR “stutterers”[All Fields]) OR “stuttering”[MeSH Terms]) OR “stuttering”[All Fields]) OR “stammer”[All Fields]) OR “stammering”[All Fields]) OR “stutter”[All Fields]) OR “stuttered”[All Fields]) OR “stutters”[All Fields]) OR “stutterings”[All Fields])
10
Myoclonus ((((((“valproate”[All Fields] OR “valproate’s”[All Fields]) OR “valproates”[All Fields]) OR “valproic acid”[MeSH Terms]) OR (“valproic”[All Fields] AND “acid”[All Fields])) OR “valproic acid”[All Fields]) OR “valproate”[All Fields]) AND (((“myoclonias”[All Fields] OR “myoclonus”[MeSH Terms]) OR “myoclonus”[All Fields]) OR “myoclonia”[All Fields])
345
Restless legs syndrome
((((((“valproate”[All Fields] OR “valproate’s”[All Fields]) OR “valproates”[All Fields]) OR “valproic acid”[MeSH Terms]) OR (“valproic”[All Fields] AND “acid”[All Fields])) OR “valproic acid”[All Fields]) OR “valproate”[All Fields]) AND ((“restless legs syndrome”[MeSH Terms] OR ((“restless”[All Fields] AND “legs”[All Fields]) AND “syndrome”[All Fields])) OR “restless legs syndrome”[All Fields])
17
Akathisia ((((((“valproate”[All Fields] OR “valproate’s”[All Fields]) OR “valproates”[All Fields]) OR “valproic acid”[MeSH Terms]) OR (“valproic”[All Fields] AND “acid”[All Fields])) OR “valproic acid”[All Fields]) OR “valproate”[All Fields]) AND ((((“akathisias”[All Fields] OR “psychomotor agitation”[MeSH Terms]) OR (“psychomotor”[All Fields] AND “agitation”[All Fields])) OR “psychomotor agitation”[All Fields]) OR “akathisia”[All Fields])
122
Tremor ((((((“valproate”[All Fields] OR “valproate’s”[All Fields]) OR “valproates”[All Fields]) OR “valproic acid”[MeSH Terms]) OR (“valproic”[All Fields] AND “acid”[All Fields])) OR “valproic acid”[All Fields]) OR “valproate”[All Fields]) AND (((((“trembling”[All Fields] OR “tremor”[MeSH Terms]) OR “tremor”[All Fields]) OR “tremors”[All Fields]) OR “tremoring”[All Fields]) OR “tremorous”[All Fields])
222
Chorea ((((((“valproate”[All Fields] OR “valproate’s”[All Fields]) OR “valproates”[All Fields]) OR “valproic acid”[MeSH Terms]) OR (“valproic”[All Fields] AND “acid”[All Fields])) OR “valproic acid”[All Fields]) OR “valproate”[All Fields]) AND ((“chorea”[MeSH Terms] OR “chorea”[All Fields]) OR “choreas”[All Fields])
124
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Category Search terms Results
Restlessness ((((((“valproate”[All Fields] OR “valproate’s”[All Fields]) OR “valproates”[All Fields]) OR “valproic acid”[MeSH Terms]) OR (“valproic”[All Fields] AND “acid”[All Fields])) OR “valproic acid”[All Fields]) OR “valproate”[All Fields]) AND ((((“psychomotor agitation”[MeSH Terms] OR (“psychomotor”[All Fields] AND “agitation”[All Fields])) OR “psychomotor agitation”[All Fields]) OR “restlessness”[All Fields]) OR “restless”[All Fields])
124
Ataxia ((((((“valproate”[All Fields] OR “valproate’s”[All Fields]) OR “valproates”[All Fields]) OR “valproic acid”[MeSH Terms]) OR (“valproic”[All Fields] AND “acid”[All Fields])) OR “valproic acid”[All Fields]) OR “valproate”[All Fields]) AND ((“ataxia”[MeSH Terms] OR “ataxia”[All Fields]) OR “ataxias”[All Fields])
205
Ballism ((((((“valproate”[All Fields] OR “valproate’s”[All Fields]) OR “valproates”[All Fields]) OR “valproic acid”[MeSH Terms]) OR (“valproic”[All Fields] AND “acid”[All Fields])) OR “valproic acid”[All Fields]) OR “valproate”[All Fields]) AND ((“dyskinesias”[MeSH Terms] OR “dyskinesias”[All Fields]) OR “ballism”[All Fields])
542
Hyperkinetic ((((((“valproate”[All Fields] OR “valproate’s”[All Fields]) OR “valproates”[All Fields]) OR “valproic acid”[MeSH Terms]) OR (“valproic”[All Fields] AND “acid”[All Fields])) OR “valproic acid”[All Fields]) OR “valproate”[All Fields]) AND (“hyperkinetic”[All Fields] OR “hyperkinetics”[All Fields])
20
Hypokinetic ((((((“valproate”[All Fields] OR “valproate’s”[All Fields]) OR “valproates”[All Fields]) OR “valproic acid”[MeSH Terms]) OR (“valproic”[All Fields] AND “acid”[All Fields])) OR “valproic acid”[All Fields]) OR “valproate”[All Fields]) AND ((“hypokinesia”[MeSH Terms] OR “hypokinesia”[All Fields]) OR “hypokinetic”[All Fields])
9
Bradykinesia ((((((“valproate”[All Fields] OR “valproate’s”[All Fields]) OR “valproates”[All Fields]) OR “valproic acid”[MeSH Terms]) OR (“valproic”[All Fields] AND “acid”[All Fields])) OR “valproic acid”[All Fields]) OR “valproate”[All Fields]) AND (((“hypokinesia”[MeSH Terms] OR “hypokinesia”[All Fields]) OR “bradykinesia”[All Fields]) OR “bradykinesias”[All Fields])
12
Movement disorder
((((((“valproate”[All Fields] OR “valproate’s”[All Fields]) OR “valproates”[All Fields]) OR “valproic acid”[MeSH Terms]) OR (“valproic”[All Fields] AND “acid”[All Fields])) OR “valproic acid”[All Fields]) OR “valproate”[All Fields]) AND ((((“movement disorders”[MeSH Terms] OR (“movement”[All Fields] AND “disorders”[All Fields])) OR “movement disorders”[All Fields]) OR (“movement”[All Fields] AND “disorder”[All Fields])) OR “movement disorder”[All Fields])
466
Total 3043
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of all papers found in the initial search. Disagreements between the authors were resolved through discussion.
Cases where the cause of MD was already known and either motor symptoms did not worsen or were not related to VPA were excluded. Also, cases that were not accessible by electronic methods, even after a formal request to the authors (by e-mail) were excluded. Reports that had more than one factor contributing to the MD were evaluated by the probability of occurrence of the event based on the Naranjo algorithm.
Data extractionFor VPA a total of 6,443 papers were found; 5,279 were irrelevant and 1,026 were unrelated to the complication, duplicate, inaccessible electronically, or provided insufficient data (Figure 3). Data abstraction was performed. When provided, we extracted author, department, year of publication, country of origin, number of patients affected, VPA indication including off-label uses, time from first VPA-dose until MD onset, time from VPA withdrawal or management to symptoms improvement, patient’s status at the last follow-up, and important findings of clinical history and management. The majority of the reports did not provide specific
Figure 3 – Flow chart of the screening process for valproate (VPA).
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information about the times of MD onset and recovery. Data were extracted by two independent authors, double-checked to ensure matching, and organized by whether or not the MD was a side effect of VPA use.
Statistical analysisCategorical variables were represented as proportions; continuous variables were represented as mean, standard deviation (SD), median, and range.
DefinitionsThe clinical characteristics and definitions of the MDs such as parkinsonism, tics, dyskinesia, dystonia, myoclonus, restless legs syndrome, akathisia, tremor, chorea, ataxia, and ballism were obtained from the reference Jankovic and Tolosa (2007). The clinical diagnosis for the psychiatric conditions was obtained from the Diagnostic and Statistical Manual of Mental Disorders (DSM-5®) (American Psychiatric Association, 2013). The Naranjo algorithm was used for determining the likelihood of whether an adverse drug reaction was actually due to the drug rather than the result of other factors (Naranjo et al., 1981). In the cases where the non-English literature was beyond the authors’ proficiency (English, Portuguese, Spanish, Italian, French, and German) and the English abstract did not provide enough data, such as Japanese, Korean, Chinese, Russian, and Dutch, Google Translate service was used (De Vries et al., 2018).
ResultsFor the years 1975 to 2019, a total of 138 reports containing 362 cases, from thirty-three countries, of individuals who developed a movement disorder (MD) secondary to valproate (VPA) were reported (Table 2). Figure 4 shows the number of reports
Figure 4 – Graphic showing the number of clinical reports of valproate (VPA)-associated movement disorders (MD) from 1975 to 2019.
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ble
2 –
Clin
ical
rep
orts
of
VPA
-ass
ocia
ted
MD
Ref
eren
ceC
ount
ry/
year
No.
of
ca
ses
Age
(m
ean)
/se
x
VPA
Follo
w-
upIm
port
ant
clin
ical
hi
stor
y (C
H)
and
clin
ical
m
anag
emen
t (C
M)
indi
cati
ondo
se
(mg)
MD
on
set
MD
re
cove
ryM
YO
CLO
NU
S
Lanc
e an
d A
ntho
nyA
ustr
alia
19
771
adul
t/F
EPI
1200
mon
ths
NA
NA
Nut
t et
al.
USA
197
91
57/M
PD10
00–
2000
33 d
ays
NA
NA
CH
: ast
erix
is
CM
: dru
g w
ithdr
awal
Bode
nste
iner
et
al.
USA
198
12
NA
EPI
NA
NA
NA
NA
Cam
post
rini
et a
l.Ita
ly 1
983
2ad
ult/
1 M
+ 1
FEP
IN
AN
AN
AN
AC
H: h
yper
amm
onem
ia
Zac
cara
et
al.
Italy
198
42
19.5
/1
M +
1 F
EPI
800
(mea
n)2
wee
ks
(mea
n)4
days
CR
CH
: ast
erix
is, o
ne c
ortic
al, o
ther
su
bcor
tical
; app
aren
tly t
hres
hold
-eff
ect.
CM
: in
one
patie
nt t
he
MC
L ap
pear
ed a
fter
a do
se
incr
ease
. The
dos
e w
as r
educ
ed
but
the
sym
ptom
s pe
rsis
ted.
V
PA w
ithdr
awal
with
sym
ptom
s re
cove
red
Gas
taut
and
M
ege
Fran
ce 1
985
1ad
ult/
NA
EPI
NA
NA
NA
NA
CH
: hyp
eram
mon
emia
with
out
hepa
tic in
suffi
cien
cy
Agu
glia
et
al.
Italy
199
56
39.8
3/3
F +
3 M
EPI
1200
1 w
eek
2–6
days
CR
CH
: cor
tical
ast
erix
is.
CM
: VPA
with
draw
al
Vogt
and
M
othe
rsill
Switz
erla
nd
2000
343
/3 F
EPI
NA
NA
NA
CR
CH
: sub
cort
ical
, EEG
-bas
ed.
Poss
ible
inte
ract
ion
with
ox
carb
azep
ine
and
lam
otrig
ine.
C
M: d
rug
with
draw
al
149)
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Prague Medical Report / Vol. 122 (2021) No. 3, p. 140–180
Shira
saka
and
M
itsuy
oshi
Japa
n 19
991
10/F
EPI
NA
1 m
onth
wee
ksC
RC
H: c
ortic
al a
ster
ixis
; dos
e-de
pend
ent
effec
t: do
se in
crea
se
caus
ed a
n in
crea
se o
f M
CL
freq
uenc
y: V
PA w
ithdr
awal
Rot
tach
et
al.
Ger
man
y 20
001
28/N
ABD
600
2 w
eeks
4 da
ysC
RC
H: c
ortic
al a
ster
ixis,
EEG
-bas
ed.
CM
: VPA
with
draw
al
Kao
et
al.
Taiw
an
2001
151
/FEP
I15
002
wee
ks<
1 w
eek
CR
CH
: sub
cort
ical
ast
erix
is;
hype
ram
mon
emia
; pos
sibl
e in
tera
ctio
n w
ith C
BZ. C
M: V
PA
with
draw
al
Rei
f et
al.
Ger
man
y 20
041
42/M
DPS
2000
7 da
y2
days
CR
CH
: cor
tical
MC
L, E
EG-b
ased
. C
M: V
PA w
ithdr
awal
Bref
el-
Cou
rbon
et
al.
Fran
ce
2006
20N
AN
AN
AN
AN
AN
A
Dea
lber
to a
nd
Sara
zin
Can
ada
2008
141
/Fm
ood
1000
1 ye
ar2
days
CR
CH
: cor
tical
ast
erix
is, E
EG-b
ased
; hy
pera
mm
onem
ia. C
M: V
PA
with
draw
al
Fan
et a
l.Ta
iwan
200
81
72/F
moo
d90
03
mon
ths
1 w
eek
CR
CH
: cor
tical
ast
erix
is, E
EG-
base
d; p
ossi
ble
inte
ract
ion
with
la
mot
rigin
e; h
yper
amm
onem
ia.
CM
: VPA
with
draw
al
Yoon
et
al.
Kore
a 20
081
56.7
/MEP
IN
AN
AN
AN
A
Gar
dner
et
al.
USA
200
91
66/F
moo
d75
0N
AN
AC
RC
H: m
ultif
ocal
MC
L. C
M: V
PA
with
draw
al
Man
gew
ala
et a
l.U
SA 2
013
117
/MEP
I15
005
mon
ths
NA
no (
only
im
prov
e-m
ent
CH
: ast
erix
is; h
yper
amm
onem
ia.
CM
: VPA
-dos
e de
crea
se w
ith
part
ial i
mpr
ovem
ent
of t
he
sym
ptom
s
Nay
ak e
t al
.In
dia
2012
135
/FEP
I10
002
wee
ks<
6 w
eeks
CR
CH
: sub
cort
ical
ast
erix
is; p
ossi
ble
inte
ract
ion
with
ant
ipsy
chot
ics.
C
M: V
PA w
ithdr
awal
150)
Rissardo J. P.; Caprara A. L. F.; Durante Í.
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Ref
eren
ceC
ount
ry/
year
No.
of
ca
ses
Age
(m
ean)
/se
x
VPA
Follo
w-
upIm
port
ant
clin
ical
hi
stor
y (C
H)
and
clin
ical
m
anag
emen
t (C
M)
indi
cati
ondo
se
(mg)
MD
on
set
MD
re
cove
ry
Sure
ndra
n et
al.
Indi
a 20
161
57/M
BD15
00–
2000
7 ye
ars
3 w
eeks
CR
CH
: cor
tical
ast
erix
is, E
EG-b
ased
; hy
pera
mm
onem
ia; p
ossi
ble
inte
ract
ion
with
ris
perid
one.
C
M: V
PA w
ithdr
awal
DY
STO
NIA
Dic
k an
d Sa
unde
rsU
SA 1
980
1ad
ult/
MD
TN
600–
1800
days
–w
eeks
NA
NA
CH
: wor
seni
ng o
f ce
rvic
al +
axi
al
DT
N. C
M: V
PA w
ithdr
awal
Kiu
ru a
nd
Iivan
aine
nFi
nlan
d 19
871
23/F
EPI
1200
–15
00m
onth
s1
wee
kC
RC
H: a
xial
DT
N t
hat
occu
rred
af
ter
a do
se in
crea
se. P
revi
ous
hist
ory
of h
epat
opat
hy d
ue
to C
BZ +
VPA
+ ly
nest
reno
l in
tera
ctio
n. C
M: V
PA-d
ose
decr
ease
d w
ith t
he r
esol
utio
n
of t
he s
ympt
oms
Dun
ayev
ich
and
Stra
kow
ski
USA
199
91
40/F
schi
zo-
phre
nia
1250
7 m
onth
sN
Ano
CH
: cho
reoa
thet
otic
DK
N +
(b
leph
aros
pasm
+ o
rom
andi
bula
r +
cer
vica
l) D
TN
; pos
sibl
e in
tera
ctio
n w
ith o
lanz
apin
e;
prev
ious
his
tory
of
blep
haro
spas
m
with
loxa
pine
. CM
: ola
nzap
ine-
dose
dec
reas
e an
d cl
ozap
ine
star
ted
with
par
tial r
ecov
ery
Oh
et a
l.Ko
rea
2004
140
/MEP
I12
00da
ys1
wee
kC
RC
H: s
pasm
odic
dys
phon
ia.
CM
: VPA
-dos
e re
duct
ion
with
the
re
cove
ry o
f th
e sy
mpt
oms
Teiv
e et
al.
Braz
il 20
04a
18/
MEP
IN
AN
AN
AN
AC
H: V
PA w
as p
rese
nt w
hen
the
stat
us D
TN
occ
urre
d
151)
VPA-associated MD
Prague Medical Report / Vol. 122 (2021) No. 3, p. 140–180
Wer
ner
et a
l.Sw
itzer
land
20
061
elde
rly/
NA
NA
NA
NA
NA
NA
CH
: pos
sibl
e di
ffere
ntia
l with
D
TN
; dro
pped
hea
d sy
ndro
me
was
mor
e se
vere
in p
atie
nts
usin
g V
PA
Yoha
nan
et a
l.U
SA 2
006
165
/Msc
hizo
-ph
reni
a15
00se
vera
l m
onth
sw
eeks
CR
CH
: axi
al D
TN
; pos
sibl
e in
tera
ctio
n w
ith C
BZ +
ris
perid
one.
CM
: VPA
with
draw
al
Hab
erm
eyer
et
al.
Switz
erla
nd
2007
160
/Fm
ood
900
4 da
ysN
AC
RC
H: a
xial
DT
N (
ante
roco
llis)
. C
M: V
PA a
nd q
uetia
pine
-dos
e de
crea
se a
nd b
iper
iden
sta
rted
w
ith s
ympt
oms
reco
very
Lee
et a
l.Ko
rea
2007
164
/FEP
I60
0da
ysN
AN
AC
H: p
atie
nt w
ith p
roba
ble
Cre
utzf
eldt
-Jak
ob d
isea
se t
hat
wor
sene
d D
TN
and
MC
L w
hen
VPA
was
sta
rted
Zad
ikoff
et
al.
Can
ada
2007
247
.5/
1 F
+ 1
MEP
IN
AN
AN
AN
AC
H: o
ne t
ask
spec
ific
DT
N,
othe
r he
mi-D
TN
Cza
rnec
ki
et a
l.U
SA 2
008
159
/MBD
NA
days
NA
noC
H: a
xial
DT
N (
ante
roco
llis)
+
PKN
+ A
KT;
pos
sibl
e in
tera
ctio
n w
ith r
ispe
ridon
e +
que
tiapi
ne.
CM
: all
drug
s w
ithdr
awal
with
out
impr
ovem
ent;
he r
ecei
ved
the
diag
nosi
s of
fron
tote
mpo
ral
dem
entia
Dug
gal
USA
200
81
20/M
schi
zo-
phre
nia
1000
3 da
ys1
day
CR
CH
: axi
al D
TN
(la
tero
colli
s);
poss
ible
inte
ract
ion
with
zi
pras
idon
e. C
M: b
enzt
ropi
ne w
as
star
ted
with
an
impr
ovem
ent
of
the
sym
ptom
s
Bayr
am e
t al
.Tu
rkey
201
31
4/F
EPI
NR
6 m
onth
sN
AC
RC
H: c
ervi
cal D
TN
; pos
sibl
e in
tera
ctio
n w
ith b
utam
irate
citr
ate
152)
Rissardo J. P.; Caprara A. L. F.; Durante Í.
Prague Medical Report / Vol. 122 (2021) No. 3, p. 140–180
Ref
eren
ceC
ount
ry/
year
No.
of
ca
ses
Age
(m
ean)
/se
x
VPA
Follo
w-
upIm
port
ant
clin
ical
hi
stor
y (C
H)
and
clin
ical
m
anag
emen
t (C
M)
indi
cati
ondo
se
(mg)
MD
on
set
MD
re
cove
ry
Farid
hoss
eini
et
al.
Iran
201
51
33/F
schi
zo-
phre
nia
1000
mon
ths
1 m
onth
CR
CH
: axi
al D
TN
; pos
sibl
e in
tera
ctio
n w
ith c
loza
pine
. C
M: c
loza
pine
-dos
e re
duce
d
and
bipe
riden
sta
rted
Berm
udez
et
al.
Braz
il 20
171
62/F
BD10
003
days
NA
CR
CH
: tris
mus
, pos
sibl
e or
oman
dibu
lar
DT
N.
CM
: bip
erid
en a
nd c
lona
zepa
m
wer
e pr
escr
ibed
with
out
resp
onse
. V
PA w
ithdr
awal
with
sym
ptom
s re
solu
tion
DY
SKIN
ESI
A
Friis
et
al.
Den
mar
k 19
833
32.3
3/1
F
+ 2
Mse
vera
l14
00
(mea
n)N
AN
AN
AC
H: a
ll th
e su
bjec
ts h
ad D
KN
as
soci
ated
with
som
e de
gree
of
AK
T
Lanc
man
et
al.
USA
199
43
21/2
F
+ 1
MEP
I14
66
(mea
n)4
year
sN
AC
RC
H: 2
indi
vidu
als
wer
e in
use
of
phen
ytoi
n, p
ossi
ble
inte
ract
ion.
C
M: c
essa
tion
of V
PA o
r th
e su
bstit
utio
n to
VPA
spr
inkl
es
impr
oved
the
sym
ptom
s
Gar
a an
d R
ober
tsC
anad
a 20
002
5.37
/1
F +
1 M
EPI
1125
year
sN
AC
RC
H: o
rofa
cial
DK
N, b
ut
orom
andi
bula
r D
TN
can
not
be
excl
uded
; pos
sibl
e in
tera
ctio
n
with
met
hylp
heni
date
. C
M: P
t1 V
PA w
ithdr
awal
; Pt2
m
ethy
lphe
nida
te r
epla
ced
by
clon
idin
e
Gun
al e
t al
.Tu
rkey
200
21
38/M
EPI
1500
2 m
onth
s2
mon
ths
CR
CH
: cho
reifo
rm D
KN
. C
M: V
PA w
ithdr
awal
153)
VPA-associated MD
Prague Medical Report / Vol. 122 (2021) No. 3, p. 140–180
Hal
l and
R
inge
lU
SA 2
004
142
/Fno
nket
otic
hy
per-
gl
ycin
emia
NA
NA
NA
NA
CH
: cho
rea
in t
he p
rese
nce
of
VPA
afte
r pr
otei
n lo
adin
g; t
he
com
bina
tion
of c
hron
ic V
PA
adm
inis
trat
ion
and
a m
eal h
igh
in
prot
ein
coul
d ha
ve c
ontr
ibut
ed t
o th
e D
KN
Mor
rison
et
al.
USA
200
61
11/F
nonk
etot
ic
hype
r-
glyc
inem
ia
NA
5 da
ysN
AC
H: c
hore
iform
DK
N.
CM
: VPA
with
draw
al
Srin
ivas
an a
nd
Lok
Sing
apor
e 20
101
53/M
EPI
1900
mon
ths
2 da
ysC
RC
H: h
emic
hore
iform
DK
N; t
he
MD
occ
urre
d af
ter
one
wee
k of
VPA
-dos
e in
a d
ose
high
er
than
the
pre
scrib
ed. C
M: V
PA
with
draw
al; a
fter
VPA
rec
halle
nge
with
out
the
occu
rren
ce o
f ne
w
sym
ptom
s
van
de V
elde
et
al.
Belg
ium
20
111
80/F
mig
rain
e12
004
year
sda
ys-w
eeks
, <
6 m
onth
sC
RC
H: c
hore
iform
DK
N, w
eeks
afte
r th
e V
PA-d
ose
incr
ease
. CM
: VPA
w
ithdr
awal
and
hal
oper
idol
sta
rted
Yilm
az e
t al
.Tu
rkey
201
31
7/M
EPI
500
NA
NA
CR
CH
: oro
faci
al D
KN
afte
r 2
days
in
the
use
of m
ethy
lphe
nida
te +
VPA
Gio
rdan
o et
al.
Italy
201
41
53/F
EPI
900
days
1 w
eek
CR
CH
: cho
reifo
rm D
KN
+ a
xial
D
TN
. CM
: VPA
with
draw
al
Brun
o et
al.
UK
201
61
36/M
EPI
1000
sing
le IV
1 w
eek
CR
CH
: cho
reifo
rm D
KN
+ m
ultif
ocal
M
CL.
CM
: VPA
with
draw
al
STU
TT
ER
Bow
dle
et a
l.U
SA 1
979
222
/NA
none
1000
–15
00da
ys–
wee
ksN
AN
AC
H: t
he a
dver
se e
ffect
s st
arte
d ap
pear
ing
at 1
,000
mg.
The
sp
eaki
ng w
as c
hara
cter
ized
as
stam
mer
ing
154)
Rissardo J. P.; Caprara A. L. F.; Durante Í.
Prague Medical Report / Vol. 122 (2021) No. 3, p. 140–180
Ref
eren
ceC
ount
ry/
year
No.
of
ca
ses
Age
(m
ean)
/se
x
VPA
Follo
w-
upIm
port
ant
clin
ical
hi
stor
y (C
H)
and
clin
ical
m
anag
emen
t (C
M)
indi
cati
ondo
se
(mg)
MD
on
set
MD
re
cove
ryM
ukhe
rjee
et a
l.In
dia
2015
156
/MBD
1500
1 w
eek
< 1
wee
kC
RC
H: h
is a
rtic
ulat
ion,
inte
nsity
, tim
ings
of
utte
ranc
e, r
hyth
m w
ere
affec
ted.
CM
: VPA
with
draw
al;
VPA
rec
halle
nge
caus
ed s
ympt
oms
reap
pear
ance
AK
AT
HIS
IA
Clo
sSc
otla
nd
2001
138
/FBD
1200
1 m
onth
NA
noC
H: p
ossi
ble
inte
ract
ion
with
lit
hium
. CM
: VPA
with
draw
al
with
par
tial i
mpr
ovem
ent
of t
he
sym
ptom
s
TIC
Alo
nso-
Nav
arro
et
al.
Spai
n 20
071
14/M
EPI
1500
1 da
yN
AC
RC
H: m
otor
+ p
honi
c tic
s.
CM
: zip
rasi
done
sta
rted
with
the
im
prov
emen
t of
the
sym
ptom
s
Zad
ikoff
et
al.
Can
ada
2007
147
/MEP
IN
AN
AN
AN
AC
H: e
xces
sive
eye
blin
king
Tho
me-
Souz
a et
al.
Braz
il 20
121
18/F
EPI
1000
1.2
year
sN
AC
RC
H: m
otor
tic
s; p
ossi
ble
inte
ract
ion
with
lam
otrig
ine.
C
M: l
amot
rigin
e an
d V
PA-
dose
dec
reas
e w
ith s
ympt
oms
impr
ovem
ent
PAR
KIN
SON
ISM
Laut
in e
t al
.U
SA 1
979
152
/Msc
hizo
- ph
reni
a10
004
days
2 da
ysC
RC
H: h
e ha
d a
hist
ory
of
met
oclo
pram
ide
and
halo
perid
ol
deve
lopi
ng P
KN
. CM
: ben
ztro
pine
an
d tr
ihex
yphe
nidy
l sta
rted
with
sy
mpt
oms
perm
anen
ce. V
PA w
as
with
draw
al
155)
VPA-associated MD
Prague Medical Report / Vol. 122 (2021) No. 3, p. 140–180
Nut
t et
al.
USA
197
94
56.6
/2 F
+
2 M
PD20
0028
day
sN
AN
AC
H: t
he fo
ur p
atie
nts
deve
lope
d w
orse
ning
of
PKN
feat
ures
. Tw
o de
velo
ped
MC
L.
CM
: dru
g w
ithdr
awal
; afte
r th
e st
udy,
the
dos
es o
f th
ese
subj
ects
aff
ecte
d ne
eded
to
be s
igni
fican
tly
incr
ease
d
Friis
et
al.
Den
mar
k 19
8311
37/1
F +
10
Mse
vera
l17
00N
AN
AN
AC
H: a
ll th
e su
bjec
ts h
ad s
ome
leve
l of
AK
T a
ssoc
iate
d to
the
PK
N. 5
sub
ject
s ha
d PK
N +
D
KN
van
der
Zw
anA
ustr
alia
19
892
adul
t/N
AEP
IN
AN
AN
AC
R
Pow
er e
t al
.C
anad
a 19
901
adul
t/N
AEP
IN
AN
AN
AN
A
Alv
arez
-G
omez
et
al.
Spai
n 19
931
12/F
EPI
600
7 da
ys1
mon
thC
RC
M: V
PA r
epla
ced
by C
BZ w
ith
sym
ptom
s re
solu
tion
Froo
mes
and
St
ewar
tA
ustr
alia
19
941
67/F
EPI
1400
mon
ths
3 da
ysC
RC
H: p
ossi
ble
inte
ract
ion
with
C
BZ. C
M: C
BZ w
ithdr
awal
with
sy
mpt
oms
reso
lutio
n
Sass
o et
al.
Italy
199
42
23/2
MEP
I12
5016
mon
ths
5 w
eeks
CR
CM
: VPA
mai
nten
ance
and
sy
mpt
oms
impr
oved
ove
r tim
e
del R
eal
Fran
cia
et a
l.Sp
ain
1995
270
.5/2
FN
A15
00ye
ars
wee
ksC
RC
M: V
PA w
ithdr
awal
Arm
on e
t al
.U
SA 1
996
2751
.5/N
AEP
I14
0044
.8
mon
ths
< 3
mon
ths
CR
(96
%)
CM
: VPA
with
draw
al
Gw
inn
and
Cav
ines
sU
SA 1
997
169
/MBD
500
11 m
onth
sN
Ano
CH
: PK
N +
oro
faci
al D
KN
; po
ssib
le in
tera
ctio
n w
ith
rispe
ridon
e. C
M: d
rug
with
draw
al
with
the
per
man
ence
of
DK
N
156)
Rissardo J. P.; Caprara A. L. F.; Durante Í.
Prague Medical Report / Vol. 122 (2021) No. 3, p. 140–180
Ref
eren
ceC
ount
ry/
year
No.
of
ca
ses
Age
(m
ean)
/se
x
VPA
Follo
w-
upIm
port
ant
clin
ical
hi
stor
y (C
H)
and
clin
ical
m
anag
emen
t (C
M)
indi
cati
ondo
se
(mg)
MD
on
set
MD
re
cove
ry
Ono
frj e
t al
.Ita
ly 1
998
265
.5/1
F
+ 1
MEP
I11
506.
5 ye
ars
< 3
mon
ths
CR
CH
: in
one
of t
he p
atie
nts
a do
se
incr
ease
was
rep
orte
d 6
mon
ths
befo
re t
he M
D o
nset
; pat
ient
s as
sess
ed b
y U
nifie
d Pa
rkin
son’
s D
isea
se R
atin
g Sc
ale;
pos
sibl
e in
tera
ctio
n w
ith C
BZ
Park
-M
atsu
mot
o an
d Ta
zaw
a
Japa
n 19
983
73/2
F +
1
MEP
I80
021
mon
ths
4.3
mon
ths
CR
Con
fort
i et
al.
Italy
199
91
69/F
BD12
00<
3
mon
ths
days
–wee
ksC
RC
H: p
ossi
ble
inte
ract
ion
with
no
rtrip
tylin
e +
ven
lafa
xine
. T
he P
KN
sta
rted
with
the
add
ed
of n
ortr
ipty
line.
C
M: n
ortr
ipty
line-
dose
red
uce
impr
oved
the
sym
ptom
s
Lapi
erre
et
al.
Can
ada
1999
162
/FBD
1400
days
–w
eeks
4 da
ysC
RC
H: p
ossi
ble
PKN
mar
ked
stiff
ness
and
mot
or s
low
ness
. C
M: V
PA-d
ose
redu
ced
with
a
full
reco
very
Nou
zeill
es
et a
l.A
rgen
tina
1999
360
.33/
NA
EPI
1259
NA
NA
NA
Kim
et
al.
Kore
a 20
001
69/F
EPI
1200
2 m
onth
s<
1 m
onth
CR
Mas
mou
di
et a
l.Fr
ance
200
05
64/2
F +
3
MEP
I14
006
mon
ths–
10 y
ears
wee
ks–
mon
ths
CR
CH
: dem
entia
cha
ract
eriz
ed b
y an
in
sidi
ous
onse
t w
as a
ssoc
iate
d in
th
ree
case
s an
d br
adyp
sych
ia in
on
e ca
se. C
M: V
PA w
ithdr
awal
Shill
and
Fife
USA
200
01
67/F
EPI
NA
2 ye
ars
3 m
onth
sC
RC
H: m
ultip
le s
yste
m a
trop
hy-li
ke
synd
rom
e. C
M: V
PA w
ithdr
awal
157)
VPA-associated MD
Prague Medical Report / Vol. 122 (2021) No. 3, p. 140–180
Barr
oso
Fran
ce 2
002
172
/NA
NA
NA
NA
NA
NA
Fole
y et
al.
USA
200
26
70/6
M3
EPI +
3
BD11
66.7
21.3
m
onth
sN
AC
RC
H: g
ait
abno
rmal
ity w
as t
he m
ost
com
mon
pre
sent
ing
sym
ptom
Iijim
aJa
pan
2002
177
/Mbe
havi
or
cont
rol
300
1 w
eek
NA
CR
CM
: VPA
with
draw
al
Raj
a an
d A
zzon
iIta
ly 2
002
138
/NA
NA
NA
NA
NA
CR
CH
: pos
sibl
e PK
N a
nd in
tera
ctio
n w
ith q
uetia
pine
Rei
f et
al.
Ger
man
y 20
031
62/F
moo
d12
0010
day
s7
days
CR
CH
: pos
sibl
e in
tera
ctio
n w
ith
lithi
um; h
yper
amm
onem
ia.
CM
: VPA
and
lith
ium
with
draw
al;
aman
tadi
ne s
tart
ed
East
erfo
rd
et a
l.U
K 2
004
560
.2/4
M
+ 1
FEP
I12
20>
1 y
ear
NA
CR
(2/
5)C
H: n
orm
al β
-CIT
-SPE
CT.
C
M: V
PA w
ithdr
awal
Ferr
ari e
t al
.Ita
ly 2
004
352
.66/
3 M
EPI
1250
4.6
year
NA
CR
CH
: one
of
the
patie
nts
had
PKN
af
ter
IV V
PA; d
ose-
unre
late
d si
de
effec
t
Lee
Kore
a 20
041
61/M
BD15
00da
ys–
wee
ks<
7 d
ays
CR
CM
: PK
N p
artia
lly r
elie
ved
by t
he
coad
min
istr
atio
n of
ant
icho
liner
gic
agen
ts a
nd d
isap
pear
ed a
fter
disc
ontin
uatio
n of
VPA
Der
galu
st
et a
l.U
SA 2
005
1ad
ult/
NA
NA
NA
NA
NA
NA
Mac
phee
Scot
land
20
051
73/M
moo
d15
003
mon
ths
3 m
onth
sC
RC
H: F
P-C
IT S
PEC
T s
can
was
no
rmal
. CM
: VPA
with
draw
al
Ric
ard
et a
l.Fr
ance
200
51
58/M
BD10
007
mon
ths
1 m
onth
CR
CH
: PK
N +
cog
nitiv
e im
pair
men
t +
hyp
eram
mon
emia
. C
M: V
PA w
ithdr
awal
Thy
gese
n an
d W
olf
Den
mar
k 20
052
64/1
F +
1
MEP
I14
0010
mon
ths
wee
ksC
RC
H: P
KN
+ c
ogni
tive
impa
irm
ent.
CM
: VPA
with
draw
al
Gau
bert
et
al.
Fran
ce 2
006
182
/MEP
I20
0017
mon
ths
3 w
eeks
CR
CM
: VPA
with
draw
al
158)
Rissardo J. P.; Caprara A. L. F.; Durante Í.
Prague Medical Report / Vol. 122 (2021) No. 3, p. 140–180
Ref
eren
ceC
ount
ry/
year
No.
of
ca
ses
Age
(m
ean)
/se
x
VPA
Follo
w-
upIm
port
ant
clin
ical
hi
stor
y (C
H)
and
clin
ical
m
anag
emen
t (C
M)
indi
cati
ondo
se
(mg)
MD
on
set
MD
re
cove
ry
Ris
tić e
t al
.Se
rbia
200
65
59.9
/4
F +
1 M
EPI
1100
12.9
m
onth
sN
Ano
(on
ly
impr
ove-
men
t)
CH
: ear
ly id
entifi
catio
n of
PK
N
and
disc
ontin
uatio
n of
the
dru
g le
d to
com
plet
e re
cove
ry in
aff
ecte
d pa
tient
s
Borr
oni e
t al
.Ita
ly 2
007
161
/FEP
I12
0010
yea
rsN
Ano
(on
ly
impr
ove-
men
t)
CH
: mul
tiple
sys
tem
atr
ophy
-like
sy
ndro
me.
C
M: V
PA w
ithdr
awal
Hom
met
et
al.
Fran
ce 2
007
181
/MEP
I50
02
mon
ths
3 m
onth
sC
RC
H: p
ossi
ble
PKN
. C
M: V
PA-d
ose
decr
ease
with
out
impr
ovem
ent;
VPA
with
draw
al
with
full
reco
very
Jam
ora
et a
l.U
SA 2
007
642
.16/
4
F +
2 M
EPI
750
76.1
6 m
onth
sN
Ano
(on
ly
impr
ove-
men
t)
Mac
phee
and
St
ewar
tSc
otla
nd
2007
167
/FEP
I60
010
yea
rsN
Ano
(on
ly
impr
ove-
men
t)
CH
: FP-
CIT
SPE
CT
sca
n w
as
norm
al. C
M: V
PA w
ithdr
awal
Zad
ikoff
et
al.
Can
ada
2007
644
.5/4
F
+ 2
MEP
I14
257.
33 y
ears
NA
NA
Agu
ilar
and
Ond
oU
SA 2
008
463
.2/N
AN
AN
A71
.4
mon
ths
NA
NA
Max
imov
and
M
axim
ovBu
lgar
ia
2008
175
/MEP
I20
00N
AN
AN
oC
M: l
evod
opa
was
sta
rted
with
im
prov
emen
t of
the
sym
ptom
s
Sala
zar
et a
l.A
rgen
tina
2008
167
/Mm
ood
1000
days
2 m
onth
sC
RC
H: P
KN
+ a
xial
DT
N
(late
roco
llis)
; a h
isto
ry o
f H
untin
gton
’s d
isea
se.
CM
: VPA
with
draw
al
159)
VPA-associated MD
Prague Medical Report / Vol. 122 (2021) No. 3, p. 140–180
Sech
i et
al.
Italy
200
81
39/F
pala
tal M
CL
1000
3 m
onth
s1
mon
thC
RC
H: a
his
tory
of
Ale
xand
er’s
di
seas
e. C
M: V
PA w
ithdr
awal
Torib
io-D
íaz
et a
l.Sp
ain
2008
178
/FEP
I15
002
mon
ths
2 m
onth
sC
RC
H: P
KN
+ c
ogni
tive
impa
irm
ent.
CM
: VPA
with
draw
al
Abr
eu e
t al
.Br
azil
2009
147
/FBD
2500
7 m
onth
sN
Ano
(on
ly
impr
ove-
men
t)
CH
: PK
N +
cog
nitiv
e im
pair
men
t. C
M: V
PA w
ithdr
awal
Lidb
om e
t al
.Sw
eden
20
091
72/F
moo
d14
0011
yea
rsN
AN
AC
H: P
KN
+ c
ogni
tive
impa
irm
ent.
CM
: VPA
with
draw
al
Lout
er a
nd
Trom
pN
ethe
rland
s 20
091
57/F
NA
NA
NA
NA
NA
Schr
eur
et a
l.N
ethe
rland
s 20
092
70/2
MEP
I85
02.
5 ye
ars
NA
CR
CH
: PK
N +
cog
nitiv
e im
pair
men
t. C
M: V
PA w
ithdr
awal
And
rade
et
al.
Cub
a 20
101
52/F
EPI
1140
2 m
onth
s2
mon
ths
CR
CH
: PK
N +
cog
nitiv
e im
pair
men
t. C
M: V
PA w
ithdr
awal
Khw
aja
et a
l.In
dia
2010
126
/FEP
I10
002
year
s3
mon
ths
CR
CH
: pro
gres
sive
sup
ranu
clea
r pa
lsy-
like
synd
rom
e.
CM
: VPA
with
draw
al
Lyel
l et
al.
UK
201
02
76/N
AN
AN
AN
AN
AN
A
Mun
hoz
et a
l.Br
azil
2010
1367
.6/N
AN
AN
AN
AN
AN
A
Peno
t an
d Pr
adea
uFr
ance
201
01
75/F
EPI
1000
1 w
eek
2 m
onth
sC
RC
H: p
ossi
ble
PKN
+ a
xial
DT
N
and
inte
ract
ion
with
asp
irin.
C
M: V
PA-d
iose
dec
reas
e w
ith t
he
impr
ovem
ent
of t
he s
ympt
oms
Slee
gers
et
al.
Net
herla
nds
2010
170
/FEP
I10
00m
onth
s5
wee
ksC
RC
H: P
KN
+ c
ogni
tive
impa
irm
ent;
a hi
stor
y of
sys
tem
ic lu
pus
eryt
hem
atou
s.
CM
: VPA
with
draw
al
Bond
on-
Gui
tton
et
al.
Fran
ce 2
011
10N
AN
AN
AN
AN
AN
A
160)
Rissardo J. P.; Caprara A. L. F.; Durante Í.
Prague Medical Report / Vol. 122 (2021) No. 3, p. 140–180
Ref
eren
ceC
ount
ry/
year
No.
of
ca
ses
Age
(m
ean)
/se
x
VPA
Follo
w-
upIm
port
ant
clin
ical
hi
stor
y (C
H)
and
clin
ical
m
anag
emen
t (C
M)
indi
cati
ondo
se
(mg)
MD
on
set
MD
re
cove
ry
Evan
s et
al.
USA
201
11
65/F
EPI
1000
13 y
ears
NA
no (
only
im
prov
e-m
ent)
CH
: PK
N +
cog
nitiv
e im
pair
men
t; no
rmal
pre
ssur
e hy
droc
epha
lus-
like
pres
enta
tion.
CM
: VPA
w
ithdr
awal
Sarn
a an
d Pr
ings
heim
Can
ada
2011
163
/FBD
NA
1–2
year
sN
Ano
(on
ly
impr
ove-
men
t)
CH
: pro
gres
sive
sup
ranu
clea
r pa
lsy-
like
synd
rom
e.
CM
: VPA
with
draw
al
Gos
ala
Raj
a K
ukku
ta e
t al
.In
dia
2013
156
/MEP
I80
06
mon
ths
4 da
ysC
RC
H: p
rogr
essi
ve s
upra
nucl
ear
pals
y-lik
e sy
ndro
me;
hy
pera
mm
onem
ia.
CM
: VPA
with
draw
al
Silv
er a
nd
Fact
orU
SA 2
013
563
/3
F +
2 M
2 D
PS +
1
MC
L +
1 B
D
+ 1
EPI
1000
1.81
m
onth
s9
mon
ths
CR
(3/
5)C
H: P
KN
+ c
ogni
tive
impa
irm
ent
(3/5
). C
M: V
PA w
ithdr
awal
Ath
auda
et
al.
UK
201
51
65/M
EPI
3000
8 ye
ars
NA
no (
only
im
prov
e-m
ent)
CH
: due
to
cont
inuo
us P
KN
sig
ns
afte
r m
anag
emen
t a
DaT
SCA
N
was
per
form
ed w
hich
sho
wed
ab
norm
al u
ptak
e an
d he
rec
eive
d th
e di
agno
sis
of id
iopa
thic
PD
. C
M: V
PA w
ithdr
awal
Jopo
wic
z an
d K
urko
wsk
a-Ja
strz
ebsk
a
Pola
nd 2
014
176
/MEP
I10
003
mon
ths
NA
no (
only
im
prov
e-m
ent)
CM
: VPA
-dos
e re
duce
with
the
im
prov
emen
t of
the
sym
ptom
s
Prak
ash
et a
l.D
enm
ark
2015
176
/FEP
I12
00ye
ars
NA
no (
only
im
prov
e-m
ent)
CH
: PK
N +
cog
nitiv
e im
pair
men
t. C
M: V
PA w
ithdr
awal
Des
ai a
nd
Des
aiIn
dia
2015
3N
AN
AN
AN
AN
AN
A
161)
VPA-associated MD
Prague Medical Report / Vol. 122 (2021) No. 3, p. 140–180
Has
sam
al
et a
l.U
SA 2
016
171
/FBD
1250
8 ye
ars
12 m
onth
sC
RC
H: P
KN
+ c
ogni
tive
impa
irm
ent.
CM
: VPA
with
draw
al
Iron
s et
al.
UK
201
51
87/M
NA
NA
NA
NA
no (
only
im
prov
e-m
ent)
CH
: mul
tiple
sys
tem
atr
ophy
-like
sy
ndro
me;
DaT
SCA
N p
ositi
ve.
CM
: VPA
with
draw
al
Bhat
tach
arje
e et
al.
UK
201
61
54/M
BDN
AN
AN
Ano
(on
ly
impr
ove-
men
t)
CH
: PK
N t
hat
pers
iste
d af
ter
man
agem
ent;
DaT
SCA
N p
ositi
ve.
CM
: VPA
with
draw
al
Bott
uri e
t al
.Ita
ly 2
016
159
/MEP
I90
03
mon
ths
3 m
onth
sC
RC
H: a
xial
DT
N +
PK
N;
hype
ram
mon
emia
. C
M: V
PA w
ithdr
awal
Sim
ões
et a
l.Po
rtug
al
2016
872
/6
M +
2 F
6 EP
I + 2
ps
ychi
tric
co
nditi
on
1379
4 m
onth
s8
mon
ths
CR
CM
: VPA
with
draw
al
Tada
et
al.
Japa
n 20
171
75/F
BD10
006
mon
ths
NA
no (
only
im
prov
e-m
ent)
CH
: PK
N +
cog
nitiv
e im
pair
men
t. C
M: V
PA w
ithdr
awal
Bhat
tach
arje
e et
al.
UK
201
724
68/N
AN
AN
AN
AN
AN
Aas
sess
men
t of
the
DA
T-SP
ECT
sc
ans
cond
ucte
d fo
r th
e di
agno
sis
of d
rug-
indu
ced
vers
us id
iopa
thic
PK
N
Car
uana
G
aliz
ia e
t al
.U
K 2
017
160
/FEP
I17
0020
yea
rs2
wee
ksC
RC
H: P
KN
+ c
ogni
tive
im
pair
men
t; sy
mpt
oms
occu
rred
af
ter
the
with
draw
al o
f ph
enyt
oin,
so
pos
sibl
e in
tera
ctio
n ca
nnot
be
rule
d ou
t.
CM
: VPA
with
draw
al
162)
Rissardo J. P.; Caprara A. L. F.; Durante Í.
Prague Medical Report / Vol. 122 (2021) No. 3, p. 140–180
Ref
eren
ceC
ount
ry/
year
No.
of
ca
ses
Age
(m
ean)
/se
x
VPA
Follo
w-
upIm
port
ant
clin
ical
hi
stor
y (C
H)
and
clin
ical
m
anag
emen
t (C
M)
indi
cati
ondo
se
(mg)
MD
on
set
MD
re
cove
ry
Ayk
ut e
t al
.Tu
rkey
201
81
72/M
BD25
0010
yea
rs6
days
CR
CH
: PK
N +
axi
al D
TN
. C
M: V
PA w
ithdr
awal
Kim
et
al.
Kore
a 20
181
69/F
EPI
1200
3 ye
ars
1 w
eek
CR
CH
: 18F
-FP-
CIT
PET
was
nor
mal
. C
M: V
PA w
ithdr
awal
Pate
l et
al.
Indi
a 20
181
58/M
EPI
500
7 ye
ars
NR
CR
CM
: VPA
with
draw
al
Yom
toob
et
al.
USA
201
817
64.5
4/10
F
+ 7
MN
AN
A4.
3 ye
ars
NA
NA
Baiz
abal
-C
arva
llo a
nd
Alo
nso-
Juar
ez
Mex
ico
2021
235
.9/N
AEP
I13
65N
AN
AN
A
Benn
et a
nd
Ros
enU
SA 2
019
271
/2 F
1 BD
+ 1
D
PSN
A6
mon
ths
NA
CR
CH
: PK
N +
cog
nitiv
e im
pair
men
t. C
M: V
PA w
ithdr
awal
Dal
and
W
hyte
Aus
tral
ia
2019
277
.5/2
MEP
I12
002.
5 ye
ars
NA
no (
only
im
prov
e-m
ent)
CH
: PK
N, a
fter
with
draw
al t
he
patie
nts
did
not
have
rec
over
; le
vodo
pa w
as s
tart
ed a
nd t
he
PKN
alle
viat
ed.
CM
: VPA
with
draw
al
Dav
oudi
-M
onfa
red
et a
l.
Iran
201
91
54/M
moo
d15
00N
Aw
eeks
CR
CH
: pos
sibl
e PK
N +
cog
nitiv
e im
pair
men
t. C
M: V
PA w
ithdr
awal
Ran
dhaw
a an
d M
ehan
naU
SA 2
019
1N
ABD
NA
3 m
onth
sN
Ano
(on
ly
impr
ove-
men
t)
CH
: pos
sibl
e in
tera
ctio
n w
ith
rispe
ridon
e; n
orm
al D
AT-
SPEC
T
scan
eve
n af
ter
the
perm
anen
ce o
f PK
N s
ympt
oms
Kohl
hase
et
al.
Ger
man
y 20
192
61/2
MEP
I15
25ye
ars
NA
CR
CH
: PK
N; 1
hyp
eram
mon
emia
; no
rmal
DA
T-SP
ECT
sca
n.
CM
: VPA
with
draw
al
163)
VPA-associated MD
Prague Medical Report / Vol. 122 (2021) No. 3, p. 140–180
CA
SES
NO
T C
LEA
RLY
DE
FIN
ED
Lecl
air-
Vis
onne
au
et a
l.
Fran
ce 2
016
NA
PKN
Ass
essm
ent
of t
he e
ffica
cy o
f V
PA in
pro
gres
sive
sup
ranu
clea
r pa
lsy.
The
pro
gres
sive
sup
ranu
clea
r pa
lsy
ratin
g sc
ale
at 1
2 m
onth
s w
as s
igni
fican
tly h
ighe
r in
the
VPA
tha
n in
the
pla
cebo
gro
up b
ut w
as
sim
ilar
betw
een
the
two
grou
ps a
t 24
mon
ths.
Acc
ordi
ng t
o th
e au
thor
s’ t
his
stro
ngly
sug
gest
s po
or
tole
rabi
lity
due
to s
ide
effec
ts t
han
perm
anen
t ne
urol
ogic
al d
amag
e.
Wan
g et
al.
Ger
man
y 20
16N
AEP
S,
DT
N,
AK
T,
rigid
ity
Ass
essm
ent
of t
he e
ffica
cy o
f V
PA in
sch
izop
hren
ia. T
he s
tudi
es c
ompa
red
VPA
+ a
ntip
sych
otic
to
antip
sych
otic
; non
e of
the
adv
erse
effe
cts
wer
e si
gnifi
cant
. The
y en
coun
tere
d A
KT
(3/
186,
RR
1.0
6 [0
.36,
3.0
6]);
ata
xia
(2/1
15, R
R 2
.42
[0.3
7, 1
5.92
]); D
TN
(2/
130,
RR
1.0
0 [0
.30,
3.3
7]);
rig
idity
(1/
33,
RR
2.8
3 [0
.12,
64.
89])
; uns
tabl
e ga
it (1
/19,
RR
0.2
7 [0
.02,
3.3
9]).
Inte
rest
ing,
the
VPA
was
ass
ocia
ted
with
a s
igni
fican
t de
crea
se o
f D
KN
of
–3.3
1 (–
4.91
, –1.
71).
Mak
hlou
f et
al.
Tuni
sia
2018
15EP
SA
sses
smen
t of
the
inci
denc
e of
VPA
sid
e eff
ects
in a
Tun
isia
n po
pula
tion.
15
subj
ects
com
plai
ned
of
slow
ness
of
exec
utio
n of
mov
emen
ts, a
nd E
PS w
as o
bser
ved
in e
very
one
of
thes
e su
bjec
ts.
AK
T –
aka
this
ia; B
D –
bip
olar
dis
orde
r; C
BZ –
car
bam
azep
ine;
CH
– c
linic
al h
isto
ry; C
M –
clin
ical
man
agem
ent;
CR
– c
ompl
ete
reco
very
; DK
N –
dys
kine
sia;
DPS
– d
epre
ssio
n;
DT
N –
dys
toni
a; E
EG –
ele
ctro
ence
phal
ogra
m; E
PI –
epi
leps
y; E
PS –
ext
rapy
ram
idal
sym
ptom
s; F
– fe
mal
e; M
– m
ale;
MC
L –
myo
clon
us; M
D –
mov
emen
t di
sord
er; N
A –
not
ap
plic
able
/not
ava
ilabl
e; P
KN
– p
arki
nson
ism
; PD
– P
arki
nson
’s d
isea
se; R
R –
ris
k ra
tio; S
PEC
T –
sin
gle-
phot
on e
mis
sion
com
pute
d to
mog
raph
y; V
PA –
val
proi
c ac
id/v
alpr
oate
164)
Rissardo J. P.; Caprara A. L. F.; Durante Í.
Prague Medical Report / Vol. 122 (2021) No. 3, p. 140–180Ta
ble
3 –
Res
ume
of V
PA-a
ssoc
iate
d M
D
MD
PK
NM
CL
DT
ND
KN
Stu
tter
Tic
AK
TO
ther
sG
ener
al d
ata
Cas
es (
%)
252
(69.
61)
54 (
14.9
1)17
(4.
69)
16 (
4.41
)4
(1.1
0)3
(0.8
2)1
(0.2
7)15
(4.
14)
362
Con
ti-ne
nt(%
)
Afr
ica
00
00
00
015
(10
0)15
Aus
tral
ia0
1 (1
.85)
00
00
00
1
Asi
a17
(6.
74)
6 (1
1.11
)4
(23.
52)
3 (1
8.75
)1
(25.
00)
00
031
Euro
pe12
2 (4
8.41
)36
(66
.66)
3 (1
7.64
)6
(37.
50)
1 (2
5.00
)1
(33.
33)
1 (1
00)
017
0
N. A
mer
ica
90 (
35.7
1)11
(20
.37)
8 (4
7.05
)7
(43.
75)
2 (5
0.00
)1
(33.
33)
00
119
S. A
mer
ica
23 (
9.12
)0
2 (1
1.76
)0
01
(33.
33)
00
26
Sex
(%)
Fem
ale
74 (
29.3
6)15
(27
.77)
8 (4
7.05
)8
(50.
00)
01
(33.
33)
1 (1
00)
55.8
8
(SD
: 16.
58)
Mn:
32
.75
mo
(S
D: 3
0.05
)M
n:
2.89
mo
(S
D: 2
.79)
107
Mal
e83
(32
.93)
10 (
18.5
1)8
(47.
05)
8 (5
0.00
)2
(50.
00)
2 (6
6.66
)0
113
Unk
now
n95
(37
.69)
29 (
53.7
0)1
(5.8
8)0
2 (5
0.00
)0
014
2
Age
(y)
Mea
n
Ran
ge12
–87
10–7
24–
655.
37–8
0 22
–56
14–4
738
4–87
(Md:
61)
60.8
740
.85
40.2
630
.67
36.2
526
.33
38
VPA
-dos
e (M
n m
g)13
1512
2311
1312
7411
5012
5012
0012
96 (
SD 3
65;
Rg
300–
3000
; M
d 13
79)
*VPA
-indi
catio
nEP
I (1
23/1
72)
EPI
(27/
34)
EPI
(5/1
4)EP
I (1
0/18
)BD
(1/
4)EP
I (3/
3)BD
(1/
1)EP
I(1
70/2
46)
MD
ons
etM
ean
(y)
Ran
ge4
d –
20 y
7 d
– 7
y3
d –
7 m
o1
d –
4 y
4 d
– w
ks1
d –
1.2
y1
mo
1 d
– 20
y(M
d: 2
1.15
mo)
3.38
0.49
0.23
2.21
0.02
0.60
1 m
o
MD
rec
over
yM
ean
(mo)
Ran
ge2
d –
12 m
o2
d –
6 w
k1
d –
1 m
o2
d –
2 m
o3
d –
1 w
kN
AN
A1
d –
12 m
o(M
d: 3
mo)
3.41
0.33
0.40
0.95
0.16
NA
NA
Follo
w-u
p –
% C
R
(num
ber
of r
epor
ts)
77.0
2%(1
14/1
48)
95.2
3%(2
0/21
)81
.81%
(9/1
1)10
0%(1
1/11
)10
0%(2
/2)
100%
(2/2
)0% (0/1
)80
.61%
(158
/196
)
AK
T –
aka
this
ia; B
D –
bip
olar
dis
orde
r; C
R –
com
plet
e re
cove
ry; d
– d
ay; D
KN
– d
yski
nesi
a; D
TN
– d
ysto
nia;
EPI
– e
pile
psy;
MC
L –
myo
clon
us; M
D –
mov
emen
t di
sord
er; M
d –
med
ian;
Mn
– m
ean;
mo
– m
onth
; NA
– n
ot a
vaila
ble/
not
appl
icab
le; P
KN
– p
arki
nson
ism
; SD
– s
tand
ard
devi
atio
n; R
g –
rang
e (m
inim
um–m
axim
um);
VPA
– v
alpr
oic
acid
/va
lpro
ate;
y –
yea
r; w
k –
wee
k; in
the
“O
ther
s” s
ubgr
oup
are
case
s no
t sp
ecifi
ed a
bout
the
mov
emen
t di
sord
er s
uch
as e
xtra
pyra
mid
al s
ympt
oms;
*m
ain
VPA
-indi
catio
n (n
o/to
tal)
165)
VPA-associated MD
Prague Medical Report / Vol. 122 (2021) No. 3, p. 140–180
of VPA-associated MD over time. There were 170 reports from Europe, 119 North American, 31 Asian, 26 South American, 15 African, and 1 Australian. The MDs identified were parkinsonism, with 252 cases, 54 cases of myoclonus, 17 of dystonia (DTN), 16 of dyskinesia, 4 of stutters, 3 of tics, and 1 of akathisia (AKT). In the “not clearly defined group”, 15 cases of extrapyramidal symptoms, 3 of AKT, 2 of DTN, 1 of rigidity, and 1 of unstable gait were assessed.
The summary data about VPA-associated MD is provided in Table 3. Herein, we will describe the general data of all clearly defined cases.
The abnormal movements occurred in males in 51.36% of the cases. The mean and median age was 55.8 (SD: 16.58) and 61 years (age range: 4–87 years). The indication of VPA in descending order of frequency was epilepsy 69.10% (170/246), bipolar disorder (25), “mood related” (12), DKN (dyskinesia) in Parkinson’s disease (5), schizophrenia (5), depression (4), myoclonus (MCL) (2), DTN (1), migraine (1), twitch eyelids (1), and others non-specified psychiatric conditions (20).
The mean and median time from starting VPA use to the MD onset was 32.75 (SD: 30.05) and 21.15 months (MD onset time range: 1 day – 20 years), respectively. About 75% of the individual had abnormal movement within 50 months of the VPA treatment. The mean and median time from the VPA withdrawal until the MD recovery was 2.89 (SD: 2.79) and 3 months (MD recovery time range: 1 day – 12 months), respectively. In the subgroup of subjects that had improvement of the symptoms, the complete recovery was achieved within 9 months of the drug withdrawal in almost all cases (99%). Figure 5 shows a comparison between the percentage of patients who developed a MD since the beginning of the treatment and the percentage of patients recovering after drug withdrawal when outliers were removed.
Figure 5 – Comparison between the percentage of patients developing movement disorders (MD) since the beginning of the drug treatment and the percentage of patients recovering after drug withdrawal.
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The most common management was drug withdrawal. Other options were the VPA-dose reduction, replacement of the drug probably interacting with VPA, and the prescription of other drugs after the VPA discontinuation, such as levodopa, benztropine, benzodiazepines, biperiden, haloperidol, and diphenhydramine. In addition, the replacement of VPA in tablet form for the same dosage in sprinkles presentation was sufficient to improve the symptoms in one case. A complete recovery was observed in 80.61% of the patients (158/196).
DiscussionGeneralVPA-associated MD was widely reported in the literature. We believe that the availability, costs, and some historical factors of VPA probably had contributed to this. VPA is among the safest and most effective medicines needed in a health system, as attested by the World Health Organization’s List of Essential Medicines, and it is marketed in the majority of countries. Also, VPA was the 126th most prescribed medication in the USA with almost six million prescriptions in 2017 (ClinCalc, 2020). Furthermore, the well-known description of flunarizine and cinnarizine developing PKN in 1984, promoted the awareness of the drug-induced MD resulting in an increasing number of reports about all abnormal movements secondary to medications including those associated with VPA (Teive et al., 2004b).
Based on the data available in Table 2, we can hypothetically illustrate a case. A middle-aged European male with poorly controlled epilepsy resorts to his neurologist. VPA 250 mg with a gradual increase until five-six tablets a day was prescribed. Within three years, the patient started complaining of stiffness, rigidity, and resting tremor; neurological examination revealed bradykinesia, and a diagnosis of PKN secondary to VPA was done. VPA was established and lamotrigine or carbamazepine was started. In the follow-up after three months, the patient had a full recovery and was able to walk without assistance and the tremor disappeared.
The majority of the incidences of abnormal movements associated with VPA are not well described in the literature. Table 3 is a summary of the percentages of some abnormal movements secondary to VPA (Anthony, 1977; Bowdle et al., 1979; Friis et al., 1983; Zaccara et al., 1984; van der Zwan, 1989; Armon et al., 1996; Nouzeilles et al., 1999; Easterford et al., 2004; Ristić et al., 2006; Jamora et al., 2007; Zadikoff et al., 2007; Lance and; Leclair-Visonneau et al., 2016; Makhlouf et al., 2018; Baizabal-Carvallo and Alonso-Juarez, 2021); the data was extracted from the clinical trials and population-based studies that provide sufficient data for Table 2. The incidences of VPA-associated abnormal movements extensively vary throughout the literature. For example, VPA-induced PKN was observed from 1.37 to 75% of the individuals.
Herein, we would like to discuss some of the MDs in subtopics to allow a better comprehension of the data.
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Parkinsonism (PKN)HistoryIn 1979, Lautin et al. reported the first case of VPA-induced PKN. They described a middle-aged male who was prescribed VPA 1,000 mg for schizophrenia; four days later, the patient complained of PKN symptoms. Benztropine and trihexyphenidyl were started, but the symptoms did not alleviate. Only when VPA was withdrawn the patient had a full recovery. Also, the individual had a previous history of PKN secondary to metoclopramide and haloperidol. Therefore, we believe that this has contributed significantly to the literature because a similar presentation of VPA and antidopaminergic drugs in the same individual suggested a common neuronal pathway associated with extrapyramidal symptoms of these two drug classes.It is worth mentioning that in the same year Nutt et al. (1979) published the cases of four individuals with Parkinson’s disease with worsening gait and resting tremors that were using VPA.
EpidemiologyThe incidence of PKN following VPA use found in the literature was 1.37, 1.60, 2.27, 5.04, 6.00, 10.16, 10.71, 73.33, and 75.00% (Table 4). The majority of the individuals reported were males, the mean age was 60.87 years, the mean VPA-dose was 1,315 mg. The time since starting VPA until MD onset, and the time until resolution after VPA discontinuation were 3.38 years and 3.41 months, respectively. When we compare the present study with the Brugger et al. (2016); the main differences encountered are that the present work has assessed a greater number of patients (252 vs. 116), of which the majority was male (52.86% vs. 41.4%); interestingly, the findings of Brugger et al. (2016) for mean age (63.5 years), VPA main indication (epilepsy) and median VPA dose (1,250 mg) were almost identical to those already described in this revision.
Presentation and clinical diagnosisThe presentation in the majority of the cases was a symmetric akinetic-rigid syndrome, with predominant postural/action over the resting tremor. Sometimes signs and symptoms of cognitive impairment were observed. The severity of the clinical presentation ranged from mild to severe with loss of physical independence. Some patients had pre-existing diseases other than the indication for VPA prescription such as Parkinson’s disease, multiple system atrophy, progressive supranuclear palsy, Huntington’s disease, systemic lupus erythematosus, and some brain damage. Interestingly, multiple system atrophy-like and progressive supranuclear palsy-like syndromes were reported as the presenting symptoms. A clear distinction between VPA-induced MD and idiopathic Parkinson’s disease based only on clinical criteria is challenging in clinical practice. Therefore, we proposed some clinical tools to help with the diagnosis of this syndrome (Table 5).
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Table 4 – Incidence of some abnormal movements associated with VPA in the literature
MD Reference Year NR NIncidence
(%)Studied disease
MCL Lance and Anthony 1977 1 60 1.66 EPI
Ataxia Lance and Anthony 1977 1 60 1.66 EPI
Tremor Lance and Anthony 1977 2 60 3.33 EPI
Stutter Bowdle et al. 1979 2 6 33.33 healthy
AKT Friis et al. 1983 15 15 100.00 several
PKN Friis et al. 1983 11 15 73.33 several
DKN Friis et al. 1983 8 15 53.33 several
MCL Zaccara et al. 1984 2 38 5.26 EPI
PKN van der Zwan 1989 2 88 2.27 EPI
PKN Armon et al. 1996 27 36 75.00 EPI
Tremor Armon et al. 1996 16 36 44.44 EPI
Bradykinesia Armon et al. 1996 22 35 62.85 EPI
PKN Nouzeilles et al. 1999 3 28 10.71 EPI
Intentional tremor
Nouzeilles et al. 1999 15 28 53.57 EPI
Postural tremor
Nouzeilles et al. 1999 16 28 57.14 EPI
PKN Easterford et al. 2004 3 50 6.00 EPI
Tremor Easterford et al. 2004 11 50 22.00 EPI
PKN Ristić et al. 2006 5 364 1.37 EPI
Tremor Ristić et al. 2006 28 364 7.69 EPI
Ataxia Ristić et al. 2006 7 364 1.92 EPI
PKN Jamora et al. 2007 6 119 5.04 EPI
PKN Zadikoff et al. 2007 6 59 10.16 EPI
Postural/action tremor
Zadikoff et al. 2007 6 59 10.16 EPI
DTN Zadikoff et al. 2007 2 59 3.38 EPI
Tic Zadikoff et al. 2007 1 59 1.69 EPI
Worsening of the gait
Leclair-Visonneau et al.
2016 3 28 10.71 PSP
Movements slowness
Makhlouf et al. 2018 15 74 20.27 EPI
PKNBaizabal-Carvallo and Alonso-Juarez
2021 2 125 1.60 EPI/migraine
AKT – akathisia; DKN – dyskinesia; DTN – dystonia; EPI – epilepsy; MCL – myoclonus; MD – movement disorder; N – number of individuals in the study using VPA; NR – number of reports with the movement disorder; PKN – parkinsonism; PSP – progressive supranuclear palsy; VPA – valproic acid/valproate
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Pathophysiological mechanismIn the literature, we found five possible pathophysiological mechanisms to explains the VPA-induced PKN (Figure 6) (Brugger et al., 2016). First, the VPA can increase the concentration of GABA (Löscher, 2002), which inhibits the globus pallidus connections with the thalamus, decreasing activity of the direct pathway. Second, another effect of VPA is the inhibition of the histone deacetylase that may increase the expression of some genes and decrease others such as those involved in the synaptic transmission (Löscher, 2002), which was already suggested in cell studies. Third, most affected individuals were elderly, so they may already have an imbalance of dopaminergic and cholinergic activity, and when VPA is used, a decrease in dopamine occurs, favoring the indirect pathway (Sawle et al., 1990). Fourth, VPA can, in a normal concentration of neurotransmitters (balanced state), affect mitochondrial enzymes causing cellular energy deficiency, what increases the
Table 5 – Clinical tools for the diagnosis of VPA-induced PKN
1) History of VPA use
2) PKN after therapy with VPA use (at least two of the following symptoms: bradykinesia, rigidity, and postural instability)
3) Usually, symmetrical PKN with prominent action/postural over resting tremor
4) More commonly affects elderly individuals
5) Recovery with VPA withdrawal
6) Other possible causes of PKN excluded
PKN – parkinsonism; VPA – valproic acid/valproate
Figure 6 – Schematic diagram of the possible pathophysiological mechanisms to explains the valproate (VPA)-induced parkinsonism (PKN). The first pier represented by the GABAergic and histone deacetylase effects, which are directly related to the mechanism of action of valproate (VPA). The second pier is dependent on the dopamine (DP) status of the patient that could be decreased (↓) or normal (N), in which the presence of VPA can causes a disbalance (↓↑) of dopaminergic and cholinergic activity (D/A). The third pier is those individuals with coexisting Parkinson’s disease.
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likelihood of an oxidative stress and consequently a neurodegenerative process, especially in the dopaminergic system (Löscher, 2002); a supporting fact for this theory is that individuals with particular mitochondrial lesions are more susceptible to the development of side effects related to VPA (Henry, 2003). Fifth, the diagnosis of Parkinson’s disease in a significant percentage of the patients cannot be ruled out; as a result, perhaps the use of VPA was only by chance present in these individuals, who may develop uncorrelated Parkinson’s disease.
ManagementThe most commonly reported management was the VPA discontinuation, adopted in more than seventy-five percent of the individuals. In some cases, dopamine precursors were attempted to manage and a partial improvement of the PKN symptoms was achieved; in the follow-up, levodopa showed to be effective and reduced the recovery time, but apparently these cases were after diagnosed with Parkinson’s disease. One individual received bromocriptine, but no details were provided regarding treatment response. The VPA-induced PKN had the second-worst prognosis, full recovery was obtained in 77.02% of the subjects; about 10% of subjects only had partial improvement of the symptoms, with permanence of at least one symptom even after the last follow-up.
Myoclonus (MCL)MCL was the first VPA-associated MD identified and was the second most commonly reported in the literature. The incidence of MCL related to VPA use found in the literature was 1.66–5.26% (Table 4). MCL-individuals were approximately twenty years younger than those affected by PKN, also, the VPA dose was lower, and MD onset and recovery happened sooner than in general data. The majority of the subjects involved were female (3:2). The presentation was asterixis and multifocal MCL. The MCL source was cortical and subcortical. It is worth mentioning that an important percentage of the cases only describe the neurological examination, giving the diagnosis without providing the findings of the electrodiagnostic studies. The management was drug withdrawal or the reduction of VPA-dose.
A feature reported in an important percentage of the patients, and possibly related to the mechanism of VPA-induced MCL, is the high serum concentrations of ammonia, with no sign of liver failure described in the eight individuals assessed. Therefore, some authors believe that the explanation for MCL in the group of hyperammonemic individuals is the decrease of inhibitory neurotransmitters caused by ammonia, turning the individuals more susceptible to the development of MCL (Campostrini et al., 1983; Gastaut and Mege, 1985). On the other hand, the possibility that the ammonia levels found in these cases may be incidental cannot be excluded, as clinical trials with VPA already reported higher levels of this compound in individuals without any complaint (Löscher, 2002; Bowden, 2003). Also, this
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hypothesis can support the idea that perhaps VPA action on the central nervous system may lead to the development of MCL. Moreover, we hypothesized that the mechanism behind VPA-induced MCL is probably related to VPA interaction with serotonin. In rat models, VPA caused both increase and decrease in serotonin concentration, depending on the site of action (Baf et al., 1994).
Dystonia (DTN)In the DTN group, the data obtained for doses and times until onset and recovery from MD are comparable to general data on drug-induced DTN found in literature. Dick and Saunders (1980) probably described the first case of VPA-associated DTN. They reported the case of an individual with cervical and axial DTN that they attempted to treat with VPA, and the DTN-symptoms worsened.
The presentation in descending order of frequency was axial, cervical, oromandibular, blepharospasm, status dystonicus, and spasmodic dysphonia. We included the spasmodic dysphonia in the DTN group, but some authors believe that this disorder is a different entity, which goes beyond the aim of this review (Oh et al., 2004). In the same way, dropped head syndrome commonly reported with anticonvulsants may or may not be related to DTN (Werner et al., 2006). Possible interactions with clozapine, risperidone, quetiapine, and butamirate citrate were described.
One of the possible assumptions to explain the VPA-induced DTN is based on the GABAergic neurotransmission (Löscher, 2002). We believe that due to increased GABA levels by VPA the direct and indirect pathways that go to the thalamus might be interrupted. But the indirect pathway subactivity could probably predominate, and this disruption can increase the thalamocortical drive and eventually lead to DTN (Rissardo and Caprara, 2019). Another hypothesis related to dopaminergic activity in a mechanism similar to that proposed for the VPA-induced PKN can also be assumed (Brugger et al., 2016).
Dyskinesia (DKN)Friis et al. (1983) reported in 53.33% of the individuals receiving VPA the development of DKN (Table 4). The presentation was orofacial, choreiform, hemichoreiform, and choreoathetotic. The association with another MD was observed with axial DTN and multifocal MCL. The DKN, stutter, and tics had the best prognosis with 100% recovery after the management.
The effects of VPA in the dopaminergic system probably explain the VPA-induced DKN. One fact that can support this hypothesis is the long time from starting VPA treatment until the MD onset, which was after 2.21 years. It is believed that due to the dopamine blockage, antipsychotics trigger inflammatory processes and the release of reactive oxygen species causing abnormal adaptations of the striatal organization, and ultimately leading to overactivation of the direct pathway (Lepping et al., 2011).
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The most frequent management was VPA withdrawal. Another option was the VPA-dose reduction in those individuals that a possible interaction related to protein intake or other medications was assumed. Moreover, Lancman et al. (1994) reported in one subject the substitution from VPA tablet to sprinkles improving the symptoms. A possible relation with the higher VPA plasma concentration and the DKN occurrence can be proposed in this case, since the sprinkles have their peak within four hours and other VPA formulation in one hour, especially the syrup (Cloyd et al., 1992).
Stutter, tic, and akathisia (AKT)In our analysis, we included stutter because of the possible differential diagnosis of DTN, MCL, and even DKN due to poor description of the neurological examination. It was observed only in young adult males with bipolar disorder. The MD’s times of onset and recovery were the shortest, and the VPA-dose was the lowest reported in relation to the general data. These features can support the assumption of possible DTN diagnosis. Also, the prognosis was excellent, with 100% recovery. The most effective treatment was the drug withdrawal. Mukherjee et al. (2015) attempted the VPA reintroduction, which caused the reappearance of the symptoms. Thus, in the VPA-induced stuttering, we believe that the rechallenge of VPA should not be done.
Tics were observed in three individuals and corresponded to less than one percent of VPA-induced MD reports. In the data extraction of the Zadikoff et al. (2007) study, the percentage of individuals developing tics with VPA use was 1.69%. The patients presented with motor, motor and phonic, or only excessive eye blinking tics. Two cases reported had possible drug interactions, so a clear association can only be suspected. The drugs interacting with VPA were ziprasidone and lamotrigine; VPA can increase the levels of ziprasidone/lamotrigine by decreasing their metabolism (Alonso-Navarro et al., 2007; Thome-Souza et al., 2012). The VPA-dose decrease was enough for the achievement of a full recovery in the reports.
The less frequent MD published in the literature in association with VPA was AKT. But, it is noteworthy that this does not represent clinical practice. Friis et al. (1983) assessed 15 individuals using VPA, all of them developed some degree of AKT. Clos (2001) reported the case of a young adult female with bipolar disorder who was prescribed VPA 1,200 mg, and within one month she developed AKT-symptoms, but the diagnosis may be doubtful because the individual was in concomitant use of lithium.
ConclusionIn sum, VPA-associated MD was extensively reported in the literature probably due to availability, costs, and some historical factors of VPA. The most frequent and well described MD was PKN. In descending order of frequency, the following MD related
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to VPA were encountered: PKN > MCL > DTN > DKN > Stutter > Tic > AKT. Further studies are warranted to elucidate the occurrence of these MD associated with VPA and its underlying pathophysiology. Future reports need to clearly describe the clinical history of the patient considering a full investigation of other adverse events during their entire life as well as a long-term follow-up. We believe that the knowledge of VPA-associated MD raises the awareness about MD, and especially those drug-induced, which sometimes are challenging in the clinical practice to diagnose and manage.
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